Neurology Basic and Translational Research Programs and Laboratories
We are interested in understanding how immune responses promote neurological disease. Recent advances in human genetics, particularly for neurodegenerative disorders like Alzheimer’s disease, have highlighted a causal role of disrupted immune responses in disease pathogenesis. An injurious immune response may be a common denominator across many neurological disorders, both acute (brain trauma or stroke) and chronic (epilepsy, Parkinson’s disease, Alzheimer's for eg.). An understanding of how innate immune responses cause neurological disease will be essential if we are to develop disease-modifying therapies for our patients. Using systems biology approaches, we are identifying immune pathways that regulate immune metabolism and immune responses at the brain interface. Our objectives are (1) to understand how aberrant brain and/or peripheral innate immune responses cause synapse loss and contribute to the vulnerability of selected circuits in different neurologic disorders, and (2) to develop preventive and therapeutic strategies targeting these inflammatory pathways in patients with neurologic diseases.
Within the Department of Neurology at Stanford University, Fiona Baumer's lab aims to better understand the relationship between various forms of pediatric epilepsy, cognition and learning.
We specifically research benign rolandic epilepsy (BECTs) and absence epilepsy. We hope to better understand how differences in brain excitation, plasticity and connectivity relate to difficulty with language, attention and learning in these conditions.
The Bronte-Stewart Lab investigates the brain’s contribution to abnormal movement in human subjects, using synchronous brain recordings and quantitative kinematics, and how these are modulated with different frequencies and patterns of neurostimulation. Dr. Bronte-Stewart’s team was the first in the United States to implant a sensing neurostimulator and now have the largest cohort of implanted patients in the world. From these devices, they can record brain signals directly, and use the patient’s own neural activity to drive the first closed loop neurostimulation studies in Parkinson’s disease. This work has led to the first multicenter national clinical trial in closed loop deep brain stimulation for people with Parkinson’s disease, which Dr. Bronte-Stewart will lead. Other clinical trials conducted include a study of the neurodegeneration in HIV infection and the safety of young plasma infusions as a potential treatment for Parkinson's disease.
The Day Lab focuses on defining the central nervous system features of neuromuscular disorders, which severely impact patients and families but have been incompletely investigated, explained or managed. Detailed neuropsychological and brain MRI studies help define the developmental and progressive CNS aspects of these conditions, for which we then seek molecular and cellular explanations through cell-based studies of patient-derived specimens. To assure our research is translatable to clinical practice, we are simultaneously involved in collaborative clinical research on novel treatments for neuromuscular disease, including antisense oligonucleotides and pharmacologic manipulation of muscle function, viral gene therapies and cell-based treatments.
The Ding lab uses interdisciplinary approaches to dissect the functional organization of motor circuits, particularly cortico-thalamo-basal ganglia networks. The long-term scientific goal of the Ding Lab is to construct functional circuit diagrams and establish causal relationships between activity in specific groups of neurons, circuit function, animal motor behavior and motor learing, and, thereby, to decipher how the basal ganglia process information and guide motor behavior. In addition, we aim to further help construct the details of psychomotor disorder 'circuit diagrams,' such as changes in Parkinson's disease, drug abuse and addiction.
The George lab applies bioengineering approaches to explore neurological disorders. Our particular focus is utilizing interactive biomaterials to promote neural recovery. Through the use of biomaterials, microfabrication techniques, and stem cell therapeutics, we are able to manipulate the neural environment and determine important pathways for healing. Our goal is to use these pathways to develop new treatments for patients with stroke and other neurological diseases. With nearly 800,000 strokes occurring annually in the United States alone, stroke remains a leading cause of long term disability and death in the world. Despite stroke’s prevalence, currently there are no medical therapies to improve subacute and chronic stroke recovery. The George lab strives to increase our understanding of naturally occurring repair mechanisms through biomarkers and novel technologies to improve the care of stroke survivors.
The Greicius lab uses imaging, genetics, and imaging genetics to better understand Alzheimer’s disease and related disorders from the level of molecular pathways to large-scale distributed brain networks and behavior. Recent and ongoing work leverages the APOE4 genetic variation that increases risk for Alzheimer’s disease. In the Stanford Extreme Phenotypes in Alzheimer’s Disease (StEP AD) study, the lab is looking for protective genetic variants in healthy older subjects that have 1 or 2 copies of the high-risk APOE4 gene but do not show signs of Alzheimer’s disease. The StEP AD study is also looking at the for novel causal genetic mutations in patients with early-onset Alzheimer’s disease who do not have the APOE4 variant. All participants undergo “deep phenotyping” including molecular imaging, immunophenotyping, and blood/spinal fluid biomarkers. The expectation is that novel protective or causal variants identified in the StEP AD study will provide novel targets for drug development.
Research in the Han lab mainly focuses on Multiple Sclerosis (MS) and other inflammatory demyelinating diseases of the CNS. Our goal is to identify biomarkers to monitor disease activity and to understand protective molecules that are present during neuroinflammation.
We are a translational research lab, thus we strive to directly apply our knowledge from bench to bedside. We study patient samples utilizing Systems Biology approach. We test our hypothesis in animal models, cellular and biochemical assays to decipher the molecular mechanism with the ultimate goal to apply the knowledge directly to patient care.
Within the population health sciences, our research agenda encompasses cognitive change that occurs as a usual concomitant of normal aging and the debilitating cognitive impairment that accompanies Alzheimer’s disease and other forms of dementia. Pathological changes of Alzheimer’s disease are believed to begin years, if not decades, before the onset of mental symptoms. For this reason, a key aspect of our research includes the investigation of factors that affect cognitive skills at midlife, a time when therapeutic interventions offer the greatest potential of forestalling late-life impairment. Our approach includes both investigator-initiated randomized clinical trials and population-based observational research. One important platform for our work is the Stanford Alzheimer’s Disease Research Center, a congressionally-mandated NIH center of excellence funded by the National Institute on Aging. We have also partnered with clinical epidemiologists at the University of Aarhus, Denmark, to examine risk factors for Alzheimer’s disease using linked Danish medical registries.
The Huang Lab studies the role of oxygen free radicals in oxidative tissue damage and degeneration. Our research tools include transgenic and knockout mice and tissue culture cells for in vitro gene expression.
Our research focuses on the role of redox balance in tissue maintenance and repair. Under normal metabolic conditions, oxygen free radicals are generated as by-products from oxidative phosphorylation in the mitochondria and from normal biochemical reactions in the cytosol. Oxygen free radicals are highly reactive, hence the name reactive oxygen species (ROS), and can cause damages to macromolecules, such as DNA, RNA, lipids, and proteins.
We are interested in the neuronal mechanisms that underlie synchronous oscillatory activity in the thalamus, cortex and the massively interconnected thalamocortical system. Such oscillations are related to cognitive processes, normal sleep activities and certain forms of epilepsy. Our approach is an analysis of the discrete components that make up thalamic and cortical circuits, and reconstitution of components into both in vitro biological and in silico computational networks. Accordingly, we have been able to identify genes whose products, mainly ion channels, play key roles in the regulation of thalamocortical network responses. Using this knowledge we have recently designed targeted optogenetic approaches to detect seizures at their onset, and then in real time disrupt them by instantly modifying the activity of key elements in the epileptic circuit.
The primary aim of the James Lab is to improve the diagnosis and treatment of brain diseases by developing translational molecular imaging agents for visualizing neuroimmune interactions underlying conditions such as Alzheimer’s disease, multiple sclerosis, and stroke. We are researching how the brain and its resident immune cells interact with the peripheral immune system at very early, through to late, stages of disease. Our approach involves the discovery and characterization of clinically relevant immune cell biomarkers, followed by the design of imaging agents specifically targeting these biomarkers. After preclinical validation, we translate promising imaging probes to the clinic to enable precision targeting of immunomodulatory therapeutics and real-time monitoring of treatment response.
The Knowles lab conducts basic, translational and clinical research to study how brain networks evolve in pediatric epilepsy, leading to seizures and cognitive dysfunction. We are particularly interested in how changes in white matter shape the course of epilepsy and its co-morbidities. We discovered that neuronal network dysfunction leading to generalized (absence) seizures also induces aberrant myelination that promotes seizure progression. Thus, maladaptive myelination may be a novel pathogenic mechanism in epilepsy and other neurological diseases. We use innovative neurophysiological, histological, imaging and molecular biology techniques to study multiple questions. How does white matter structure change throughout the brain over the course of epilepsy? How does white matter structure impact network synchronization, seizures and cognition? What can we learn from structural and functional changes found with various imaging modalities in children with epilepsy? Our overarching goals are to better understand how epilepsy occurs and to develop treatments that improve the lives of children with epilepsy.
The Lee Lab uses interdisciplinary approaches from biology and engineering to analyze, debug, and manipulate systems-level brain circuits. We seek to understand the connectivity and function of these large-scale networks in order to drive the development of new therapies for neurological diseases. This research finds its basic building blocks in areas ranging from medical imaging and signal processing to genetics and molecular biology.
Dr. Longo and his research team are focused on elucidating mechanisms underlying neurodegenerative disorders and developing small molecule therapeutic strategies that target these mechanisms. Neurotrophin proteins bind to multiple receptors (p75, TrkA-C) to modulate survival, functional and degenerative intracellular signaling and synaptic function. The Longo laboratory and collaborators pioneered the mechanistic principle that non-peptide small molecules targeting individual receptor epitopes can activate or modulate neurotrophin receptors to produce distinctive biological effects capable of inhibiting disease mechanisms. This work has led to successful efficacy trials in many mouse models of neurodegenerative disorders including Alzheimer’s, Huntington’s, and Parkinson’s diseases as well as spinal cord injury, traumatic brain injury, chemotherapy-induced neuropathy, ischemic stroke recovery, Rett syndrome, and epilepsy. One of our small molecules, the p75NTR ligand, LM11A-31, has progressed through a human phase 1 safety trial and is in a phase 2a Alzheimer’s disease trial ongoing in Europe. We have been fortunate to execute the rare full translational spectrum of: identifying novel basic mechanisms, creating novel entities to target those mechanisms, moving these therapeutic candidates through mouse and other pre-clinical studies, progressing one of these candidates to first-in-human safety studies and testing of the first-in-class therapeutic entity in neurodegenerative disease subjects.
The Monje Lab studies the molecular and cellular mechanisms of postnatal neurodevelopment. This includes microenvironmental influences on neural precursor cell fate choice in normal neurodevelopment and in disease states. Areas of emphasis include neuronal instruction of gliogenesis, cellular contributions to the neurogenic and gliogenic signaling microenvironment, molecular determinants of neural precursor cell fate, and the role of neural precursor cells in oncogenesis and repair mechanisms. As a practicing neurologist and neuro-oncologist, Dr Monje is particularly interested in the roles for neural precursor cell function and dysfunction in the origins of pediatric brain tumors and the consequences of cancer treatment.
Our overall research objective is to understand the risk of Alzheimer’s disease before clinical symptoms of dementia are present. To study the earliest stages of Alzheimer’s disease, we take a multimodal approach to deeply phenotype our human research volunteers. Our studies integrate information from molecular PET imaging (especially Amyloid and Tau PET), MRI scans that provide information about brain structure and function, lumbar puncture to investigate the biomarkers in the cerebrospinal fluid, sensitive neuropsychological measurements, and genetics. Our hope is that the combination of these data types will improve our ability to predict who is most at risk for dementia decades before clinical symptoms are present.
The general theme of our research is to study functional architecture of the human brain and the dynamics of activity within and between brain networks during experimental and naturalistic settings as well as during rest and sleep. Our goal is to understand the anatomical and physiological basis for human behavior and cognitive experience and how these might be affected in patients with neurological disorders.
At the Poston Lab, we seek understand the cognitive and other non-motor impairments that develop in patients with alpha-synuclein pathology, such as Parkinson’s disease, Lewy body dementia, and Multiple System Atrophy. Our lab uses functional and structural imaging, along with biological and genetic biomarkers, to determine the underlying pathophysiologies that cause these impairments, with the ultimate goal of aiding the development of new therapies.
Work in the Prince lab has focused on normal and abnormal regulation of excitability in neurons of mammalian cerebral cortex and thalamus, and mechanisms underlying development and prophylaxis of epilepsy in animal models. Long-term goals are to understand how pathological processes following traumatic brain injury, prolonged seizures and genetic mutations induce changes in structure and function of neurons and neuronal networks that lead to hyperexcitability and epileptogenesis. We have already provided proof in principal that prevention of epilepsy is possible in genetic and posttraumatic rodent models. With this information, it will be possible to devise experimental strategies that prevent epilepsy after cortical injury and other acquired and genetic abnormalities in man.
The main areas of interest of the Rando laboratory are stem cell biology, the biology of aging, and tissue engineering. We explore the basic mechanisms by which stem cells maintain and repair tissues, exploring stem cell functions from the very basic levels to clinical translation and application. Our main focus is on stem cells in skeletal muscle, but also in other tissues such as brain, skin, and blood. We seek to develop cutting edge technology to advance all aspects of our work. Beyond our basic discovery platforms, we focus also on therapeutic potential of stem cells, either by enhancing the function of endogenous cells or by developing tissue transplantation and tissue engineering approaches to restore tissue structure and function in the setting of degenerative diseases such as the muscular dystrophies, tissue aging, or injury.
A primary interest of our lab is to define lysosomal function in neurodegeneration. Lysosomes are membrane bound acidic intracellular organelles filled with hydrolytic enzymes that normally function as recycling centers within cells by breaking down damaged cellular macromolecules. Several degenerative diseases designated as lysosomal storage disorders (LSDs) are associated with the accumulation of material within lysosomes. Tay-Sachs disease, Neimann-Pick disease and Gaucher disease are some of the more common LSDs. For reasons that remain incompletely understood, these diseases often affect the nervous system out of proportion to other organs. As a model for LSDs we have studied the lysosomal free sialic acid storage disorders. These diseases are the result of a defect in transport of sialic acid across lysosomal membranes and are associated with mutations in the gene encoding the sialic acid transporter sialin. We are using molecular, genetic and biochemical approaches to better define the normal function of sialin and to determine how loss of sialin function leads to neurodevelopmental defects and neurodegeneration associated with the lysosomal free sialic acid storage disorders. We are also interested in understanding why variants in the sialin gene and other genes associated with lysosomal storage disorders such as Gaucher disease are associated with an increased risk for Parkinson disease.
The Skylar-Scott Lab is interested in assessing how cognitive, social, and physical activity affect cognitive performance and Alzheimer’s biomarkers cross-sectionally and longitudinally in a healthy older adults The lab is interested in exploring what biomarkers, demographic features, and lifestyle factors serve as “resilience factors” that correlate with superior cognitive performance. In the future, the lab hopes to investigate which lifestyle interventions prove most effective across the entire clinical continuum, from cognitively normal healthy adults to Alzheimer’s disease patients with dementia.
The Steinman laboratory is dedicated to understanding the pathogenesis of autoimmune diseases, particularly multiple sclerosis and neuromyelitis optica.
We have developed several new therapies for autoimmunity, including some in Phase 2 clinical trials in multiple sclerosis and type 1 diabetes mellitus, as well as one approved drug, natalizumab.
We have developed microarray technology for detecting autoantibodies to myelin proteins and lipids. We employ a diverse range of molecular and cellular approaches to devise new medications for demyelinating diseases, and to help predict which current medications will work at various stages of these diseases.
Thomas Südhof’s laboratory studies how synapses form in the brain, how their properties are specified, and how they accomplish the rapid and precise signaling that forms the basis for all information processing by the brain.
Our lab explores the nexus of immunology and metabolism. Our approach is unique. We leverage insights from human neurogenetic and immunogenetic disorders to unravel the molecular mechanisms of human neuroinflammation.
Genetic disorders offer an unparalleled vantage point for understanding human biology. Immunogenetic are particularly unique because immune tissue is both accessible and modifiable. These disorders offer a unique window into basic molecular mechanisms and make exceptional targets for stem cell and gene therapies.
The Wyss-Coray research team studies brain aging and neurodegeneration with a focus on age-related cognitive decline and Alzheimer’s disease. The team is studying how circulatory blood factors can modulate brain structure and function and how factors from young organisms can rejuvenate old brains. We are trying to understand the molecular basis of the systemic communication with the brain by employing a combination of genetic, cell biology, and –omics approaches in killifish, mice, and humans and through the development of bio-orthogonal tools for the in vivo labeling of proteins.
The cytoskeleton in neurons is made up of three interacting structural complexes: microfilaments (MFs), neurofilaments (NFs), and microtubules (MTs). They serve multiple roles in neurons. First, they provide structural organization for the cell interior, helping to establish metabolic compartments. Second, they serve as tracks for intracellular transport, especially axonal transport, which is critical for neuronal survival. Finally, the cytoskeleton comprises the core framework of neuronal morphologies. Disorganization of the cytoskeleton network is a prominent cytopathological feature of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and Alzheimer diseases. Our major focus is to elucidate biological functions of cytoskeletal associated proteins in neurons and to define the cellular and molecular basis for how these proteins contribute to the structure and function of neurons. Cellular and molecular approaches are being employed both in vitro and in vivo.